The field of the invention relates to benzamide compounds and therapeutic uses thereof. In particular, the field of the invention relates to novel 3-amido benzamide compounds and therapeutic uses thereof for increasing levels of APOBEC3G (A3G) and related cellular cytidine deaminases in human cells. More specifically, the disclosed 3-amido compounds could serve as therapies for diseases including but not limited to HIV infection and cancer.
Human APOBEC3G (A3G), otherwise referred to as “apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G” is an enzyme that induces hypermutation of guanosine (G) to adenine (A) in single-stranded DNA. A3G and other A3 family members (including A3F and A3H) have been shown to be inhibitors against human immunodeficiency virus type 1 (HIV-1) infection. These A3 proteins block HIV reverse transcription (RT) and integration, by causing signature “G-to-A hypermutations” in minus-strand DNA that is an intermediate in the process of RT and also by mechanisms independent of cytidine deaminase enzymatic activity. HIV virion infectivity factor (Vif) must degrade A3 proteins in HIV-infected T cells in order to produce infectious virus from those cells. However, there is natural variation in the A3-degrading function of Vif (1), and partial A3G restriction of Vif-positive HIV has been documented in vitro (2). Higher levels of APOBEC3s in the physiological range inhibit Vif-positive HIV-1 replication in cultured cells in vitro (2, 3); however, A3s only completely block replication of Vif-defective HIV-1 in vitro. In vivo, levels of HIV provirus and A3G are inversely associated (4, 5), and lower viremia and higher CD4 count are also associated with more cellular A3G in blood cells (4, 6, 7 and others). A measure of the extent of A3 cytidine deamination of HIV genomes in vivo (PBMC provirus hypermutation index) above a certain level is associated with decreased plasma HIV-1 RNA levels (4). Activity of A3G against other viruses including hepatitis B virus (HBV) has also been described. However, A3G, F, and H have not been implicated in hypermutating cellular chromosomal DNA.
A3B is not expressed at detectable levels in primary human T lymphocytes (which are the major host cells for HIV in which A3G, F, and H act), many other primary human cells and many cell lines. However, increased A3B expression has been noted in many types of cancer cells (in both cell lines in vitro and in tumor biopsy specimens). Increased A3B has been associated with increasing mutational load in genomes of these cancers. A3B over expression and enhanced cytidine deamination of human nuclear (chromosomal) DNA has been implicated in pathogenesis of several types of cancer, including cancers of breast, lung, head/neck, cervical, ovarian, bladder, prostate and multiple myeloma and certain lymphomas occurring in HIV patients (primary effusion lymphoma). A3B increases genomic mutations specifically in these cancer cells and has been called “mutagenic fuel for cancer evolution and heterogeneity” (8). While attention has been chiefly directed to inhibiting A3B cytidine deaminase activity as a therapeutic strategy, it has also been suggested that further increasing excess A3B-mediated genomic hypermutation may cause cancer cell death by synthetic lethality without harming normal cells (by analogy to effects of “mutation catastrophe” on viruses) (9, 10). It is well described that one of the essential activities of a functional p53 protein, “the guardian of the genome”, is to allow repair of potentially lethal DNA damage. Thus, we hypothesize that cancer cells lacking functional p53 will be more prone to synthetic lethality from excess A3B-mediated genome hypermutation.
There is a need for better and different treatments for HIV and cancer patients. Herein we disclose small molecules able to boost expression of A3G and related cellular proteins. These compounds could serve as therapies for the diseases in which A3G (and A3F and A3H) are a protective/defensive factor including but not limited to HIV, and could be a treatment for some cancers.